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Immunophenotypes Based on the Tumor Immune Microenvironment Allow for Unsupervised Penile Cancer Patient Stratification.

ABSTRACT: The tumor immune microenvironment (TIME) plays an important role in penile squamous cell carcinoma (peSCC) pathogenesis. Here, the immunophenotype of the TIME in peSCC was determined by integrating the expression patterns of immune checkpoints (programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), cytotoxic T lymphocyte antigen 4 (CTLA-4), and Siglec-15) and the components of tumor-infiltrating lymphocytes, including CD8+ or Granzyme B+ T cells, FOXP3+ regulatory T cells, and CD68+ or CD206+ macrophages, in 178 patients. A high density of Granzyme B, FOXP3, CD68, CD206, PD-1, and CTLA-4 was associated with better disease-specific survival (DSS). The patients with diffuse PD-L1 tumor cell expression had worse prognoses than those with marginal or negative PD-L1 expression. Four immunophenotypes were identified by unsupervised clustering analysis, based on certain immune markers, which were associated with DSS and lymph node metastasis (LNM) in peSCC. There was no significant relationship between the immunophenotypes and high-risk human papillomavirus (hrHPV) infection. However, the hrHPV-positive peSCC exhibited a higher density of stromal Granzyme B and intratumoral PD-1 than the hrHPV-negative tumors (p = 0.049 and 0.002, respectively). In conclusion, the immunophenotypes of peSCC were of great value in predicting LNM and prognosis, and may provide support for clinical stratification management and immunotherapy intervention.

SUBMITTER: Chu C

PROVIDER: S-EPMC7407624 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Immunophenotypes Based on the Tumor Immune Microenvironment Allow for Unsupervised Penile Cancer Patient Stratification.

Chu Chengbiao C Yao Kai K Lu Jiangli J Zhang Yijun Y Chen Keming K Lu Jiabin J Zhang Chris Zhiyi CZ Cao Yun Y

Cancers 20200704 7

The tumor immune microenvironment (TIME) plays an important role in penile squamous cell carcinoma (peSCC) pathogenesis. Here, the immunophenotype of the TIME in peSCC was determined by integrating the expression patterns of immune checkpoints (programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), cytotoxic T lymphocyte antigen 4 (CTLA-4), and Siglec-15) and the components of tumor-infiltrating lymphocytes, including CD8+ or Granzyme B+ T cells, FOXP3+ ...[more]

PMID: 32635549

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Project description:The host's immune system plays a pivotal role in many tumor types, including squamous cell carcinomas (SCCs). We aim to identify immunological prognosticators for lymph node metastases (LNM) and disease-specific survival (DSS) in penile SCC. For this retrospective observational cohort study, penile SCC patients (n?=?213) treated in the Netherlands Cancer Institute, were selected if sufficient formalin-fixed, paraffin-embedded tumor material was available. Analysis included previously described high-risk human papilloma virus (hrHPV) status, immunohistochemical scores for classical and non-classical human leukocyte antigen (HLA) class I, programmed death ligand-1 (PD-L1) expression, and novel data on tumor-infiltrating macrophages and cytotoxic an regulatory T-cells. Clinicopathological characteristics and extended follow-up were also included. Regression analyses investigated relationships of the immune parameters with LNM and DSS. In the total cohort, diffuse PD-L1 tumor-cell expression, CD163+ macrophage infiltration, non-classical HLA class I upregulation, and low stromal CD8+ T-cell infiltration were all associated with LNM. In the multivariable model, only tumor PD-L1 expression remained a significant predictor for LNM (odds ratio (OR) 2.8, p?=?0.05). hrHPV negativity and diffuse PD-L1 tumor-cell expression were significantly associated with poor DSS and remained so upon correction for clinical parameters [hazard ratio (HR) 9.7, p?<?0.01 and HR 2.8, p?=?0.03]. The only immune factor with different expression in HPV+ and HPV- tumors was PD-L1, with higher PD-L1 expression in the latter (p?=?0.03). In the HPV- cohort (n?=?158), LNM were associated with diffuse PD-L1 tumor-cell expression, high intratumoral CD163+ macrophage infiltration, and low number of stromal CD8+ T-cells. The first two parameters were also linked to DSS. In the multivariable regression model, diffuse PD-L1 expression remained significantly unfavorable for DSS (HR 5.0, p?<?0.01). These results emphasize the complexity of the tumor microenvironment in penile cancer and point toward several possible immunotherapy targets. Here described immune factors can aid risk-stratification and should be evaluated in clinical immunotherapy studies to ultimately lead to patient tailored treatment.

Project description:Glioma is the most common primary brain tumor, characterized by a consistently high patient mortality rate and a dismal prognosis affecting both survival and quality of life. Substantial evidence underscores the vital role of the immune system in eradicating tumors effectively and preventing metastasis, underscoring the importance of cancer immunotherapy which could potentially address the challenges in glioma therapy. Although glioma immunotherapies have shown promise in preclinical and early-phase clinical trials, they face specific limitations and challenges that have hindered their success in further phase III trials. Resistance to therapy has been a major challenge across many experimental approaches, and as of now, no immunotherapies have been approved. In addition, there are several other limitations facing glioma immunotherapy in clinical trials, such as high intra- and inter-tumoral heterogeneity, an inherently immunosuppressive microenvironment, the unique tissue-specific interactions between the central nervous system and the peripheral immune system, the existence of the blood-brain barrier, which is a physical barrier to drug delivery, and the immunosuppressive effects of standard therapy. Therefore, in this review, we delve into several challenges that need to be addressed to achieve boosted immunotherapy against gliomas. First, we discuss the hurdles posed by the glioma microenvironment, particularly its primary cellular inhabitants, in particular tumor-associated microglia and macrophages (TAMs), and myeloid cells, which represent a significant barrier to effective immunotherapy. Here we emphasize the impact of inducing immunogenic cell death (ICD) on the migration of Th17 cells into the tumor microenvironment, converting it into an immunologically "hot" environment and enhancing the effectiveness of ongoing immunotherapy. Next, we address the challenge associated with the accurate identification and characterization of the primary immune profiles of gliomas, and their implications for patient prognosis, which can facilitate the selection of personalized treatment regimens and predict the patient's response to immunotherapy. Finally, we explore a prospective approach to developing highly personalized vaccination strategies against gliomas, based on the search for patient-specific neoantigens. All the pertinent challenges discussed in this review will serve as a compass for future developments in immunotherapeutic strategies against gliomas, paving the way for upcoming preclinical and clinical research endeavors.

Dataset Information

Immunophenotypes Based on the Tumor Immune Microenvironment Allow for Unsupervised Penile Cancer Patient Stratification.

Publications

Immunophenotypes Based on the Tumor Immune Microenvironment Allow for Unsupervised Penile Cancer Patient Stratification.

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